PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

被引:91
作者
Heo, Kyung-Sun [1 ]
Lee, Hakjoo [1 ]
Nigro, Patrizia [1 ]
Thomas, Tamlyn [1 ]
Le, Nhat-Tu [1 ]
Chang, Eugene [1 ]
McClain, Carolyn [1 ]
Reinhart-King, Cynthia A. [2 ]
King, Michael R. [2 ]
Berk, Bradford C. [1 ]
Fujiwara, Keigi [1 ]
Woo, Chang-Hoon [1 ]
Abe, Jun-ichi [1 ]
机构
[1] Univ Rochester, Aab Cardiovasc Res Inst, Rochester, NY 14642 USA
[2] Cornell Univ, Dept Biomed Engn, Ithaca, NY 14853 USA
基金
美国国家卫生研究院;
关键词
PROTEIN-KINASE-C; NITRIC-OXIDE SYNTHASE; SIGNAL-REGULATED KINASE-5; LAMINAR SHEAR-STRESS; KAPPA-B ACTIVATION; PEROXYNITRITE FORMATION; LESION FORMATION; GENE-EXPRESSION; GROWTH ARREST; CELL-DEATH;
D O I
10.1083/jcb.201010051
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Atherosclerosis is readily observed in regions of blood vessels where disturbed blood flow (d-flow) is known to occur. A positive correlation between protein kinase C zeta (PKC zeta) activation and d-flow has been reported, but the exact role of d-flow-mediated PKC zeta activation in atherosclerosis remains unclear. We tested the hypothesis that PKC zeta activation by d-flow induces endothelial cell (EC) apoptosis by regulating p53. We found that d-flow-mediated peroxynitrite (ONOO.) increased PKC zeta activation, which subsequently induced p53 SUMOylation, p53-Bcl-2 binding, and EC apoptosis. Both d-flow and ONOO. increased the association of PKC zeta with protein inhibitor of activated STATy (PIASy) via the Siz/PIAS-RING domain (amino acids 301-410) of PIASy, and overexpression of this domain of PIASy disrupted the PKC zeta-PIASy interaction and PKC zeta-mediated p53 SUMOylation. En face confocal microscopy revealed increases in nonnuclear p53 expression, nitrotyrosine staining, and apoptosis in aortic EC located in d-flow -areas in wild-type mice, but these effects were significantly decreased in p53(-/-) mice. We propose a novel mechanism for p53 SUMOylation mediated by the PKC zeta-PIASy interaction during d-flow-mediated EC apoptosis, which has potential relevance to early events of atherosclerosis.
引用
收藏
页码:867 / 884
页数:18
相关论文
共 59 条
[1]   The hinge-helix 1 region of peroxisome proliferator-activated receptor γ1 (PPARγ1) mediates interaction with extracellular signal-regulated kinase 5 and PPARγ1 transcriptional activation:: Involvement in flow-induced PPARγ activation in endothelial cells [J].
Akaike, M ;
Che, WY ;
Marmarosh, NL ;
Ohta, S ;
Osawa, M ;
Ding, B ;
Berk, BC ;
Yan, C ;
Abe, J .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (19) :8691-8704
[2]   Macrophage-derived peroxynitrite diffusion and toxicity to Trypanosoma cruzi [J].
Alvarez, MN ;
Piacenza, L ;
Irigoín, F ;
Peluffo, G ;
Radi, R .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2004, 432 (02) :222-232
[3]   RETRACTED: The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis (Retracted article. See vol. 80, pg. 1140, 2020) [J].
Bischof, Oliver ;
Schwamborn, Klaus ;
Martin, Nadine ;
Werner, Andreas ;
Sustmann, Claudio ;
Grosschedl, Rudolf ;
Dejean, Anne .
MOLECULAR CELL, 2006, 22 (06) :783-794
[4]   Structure and regulation of Src family kinases [J].
Boggon, TJ ;
Eck, MJ .
ONCOGENE, 2004, 23 (48) :7918-7927
[5]   C-terminal modifications regulate MDM2 dissociation and nuclear export of p53 [J].
Carter, Stephanie ;
Bischof, Oliver ;
Dejean, Anne ;
Vousden, Karen H. .
NATURE CELL BIOLOGY, 2007, 9 (04) :428-U111
[6]   SENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase 1 [J].
Cheng, JK ;
Wang, DC ;
Wang, ZX ;
Yeh, ETH .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (13) :6021-6028
[7]   A DOMINANT-NEGATIVE PROTEIN-KINASE-C ZETA-SUBSPECIES BLOCKS NF-KAPPA-B ACTIVATION [J].
DIAZMECO, MT ;
BERRA, E ;
MUNICIO, MM ;
SANZ, L ;
LOZANO, J ;
DOMINGUEZ, I ;
DIAZGOLPE, V ;
DELERA, MTL ;
ALCAMI, J ;
PAYA, CV ;
ARENZANASEISDEDOS, F ;
VIRELIZIER, JL ;
MOSCAT, J .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (08) :4770-4775
[8]   Left ventricular hypertrophy in ascending aortic stenosis mice - Anoikis and the progression to early failure [J].
Ding, B ;
Price, RL ;
Goldsmith, EC ;
Borg, TK ;
Yan, XH ;
Douglas, PS ;
Weinberg, EO ;
Bartunek, J ;
Thielen, T ;
Didenko, VV ;
Lorell, BH .
CIRCULATION, 2000, 101 (24) :2854-2862
[9]   WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION [J].
ELDEIRY, WS ;
TOKINO, T ;
VELCULESCU, VE ;
LEVY, DB ;
PARSONS, R ;
TRENT, JM ;
LIN, D ;
MERCER, WE ;
KINZLER, KW ;
VOGELSTEIN, B .
CELL, 1993, 75 (04) :817-825
[10]   Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes [J].
Galluzzi, L. ;
Aaronson, S. A. ;
Abrams, J. ;
Alnemri, E. S. ;
Andrews, D. W. ;
Baehrecke, E. H. ;
Bazan, N. G. ;
Blagosklonny, M. V. ;
Blomgren, K. ;
Borner, C. ;
Bredesen, D. E. ;
Brenner, C. ;
Castedo, M. ;
Cidlowski, J. A. ;
Ciechanover, A. ;
Cohen, G. M. ;
De Laurenzi, V. ;
De Maria, R. ;
Deshmukh, M. ;
Dynlacht, B. D. ;
El-Deiry, W. S. ;
Flavell, R. A. ;
Fulda, S. ;
Garrido, C. ;
Golstein, P. ;
Gougeon, M-L ;
Green, D. R. ;
Gronemeyer, H. ;
Hajnoczky, G. ;
Hardwick, J. M. ;
Hengartner, M. O. ;
Ichijo, H. ;
Jaattela, M. ;
Kepp, O. ;
Kimchi, A. ;
Klionsky, D. J. ;
Knight, R. A. ;
Kornbluth, S. ;
Kumar, S. ;
Levine, B. ;
Lipton, S. A. ;
Lugli, E. ;
Madeo, F. ;
Malorni, W. ;
Marine, J-C W. ;
Martin, S. J. ;
Medema, J. P. ;
Mehlen, P. ;
Melino, G. ;
Moll, U. M. .
CELL DEATH AND DIFFERENTIATION, 2009, 16 (08) :1093-1107